Treatment systems, methods, and apparatuses for improving the appearance of skin and providing other treatments

ABSTRACT

Treatment systems, methods, and apparatuses for improving the appearance of skin or other target regions are described as well as for providing for other treatments. Aspects of the technology are directed to improving the appearance of skin by tightening the skin, improving skin tone or texture, eliminating or reducing wrinkles, increasing skin smoothness, or improving the appearance of cellulite. Treatments can include cooling a surface of a patient&#39;s skin and detecting at least one freeze event in the cooled skin. The treatment system can continue cooling the patient&#39;s skin after the freeze event(s) are detected so to maintain at least a partially frozen state of the tissue for a period of time.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application claims priority to U.S. Provisional ApplicationSer. No. 61/943,250, filed Feb. 21, 2014, U.S. Provisional ApplicationSer. No. 61/934,549, filed Jan. 31, 2014, and U.S. ProvisionalApplication Ser. No. 61/943,257, filed Feb. 21, 2014, the disclosures ofwhich are incorporated herein by reference in their entireties.

INCORPORATION BY REFERENCE OF COMMONLY-OWNED APPLICATIONS AND PATENTS

The following commonly assigned U.S. patent applications and U.S.Patents are incorporated herein by reference in their entirety:

U.S. Patent Publication No. 2008/0287839 entitled “METHOD OF ENHANCEDREMOVAL OF HEAT FROM SUBCUTANEOUS LIPID-RICH CELLS AND TREATMENTAPPARATUS HAVING AN ACTUATOR”;

U.S. Pat. No. 6,032,675 entitled “FREEZING METHOD FOR CONTROLLED REMOVALOF FATTY TISSUE BY LIPOSUCTION”;

U.S. Patent Publication No. 2007/0255362 entitled “CRYOPROTECTANT FORUSE WITH A TREATMENT DEVICE FOR IMPROVED COOLING OF SUBCUTANEOUSLIPID-RICH CELLS”;

U.S. Pat. No. 7,854,754 entitled “COOLING DEVICE FOR REMOVING HEAT FROMSUBCUTANEOUS LIPID-RICH CELLS”;

U.S. Patent Publication No. 2011/0066216 entitled “COOLING DEVICE FORREMOVING HEAT FROM SUBCUTANEOUS LIPID-RICH CELLS”;

U.S. Patent Publication No. 2008/0077201 entitled “COOLING DEVICES WITHFLEXIBLE SENSORS”;

U.S. Patent Publication No. 2008/0077211 entitled “COOLING DEVICE HAVINGA PLURALITY OF CONTROLLABLE COOLING ELEMENTS TO PROVIDE A PREDETERMINEDCOOLING PROFILE”;

U.S. Patent Publication No. 2009/0118722, filed Oct. 31, 2007, entitled“METHOD AND APPARATUS FOR COOLING SUBCUTANEOUS LIPID-RICH CELLS ORTISSUE”;

U.S. Patent Publication No. 2009/0018624 entitled “LIMITING USE OFDISPOSABLE SYSTEM PATIENT PROTECTION DEVICES”;

U.S. Patent Publication No. 2009/0018623 entitled “SYSTEM FOR TREATINGLIPID-RICH REGIONS”;

U.S. Patent Publication No. 2009/0018625 entitled “MANAGING SYSTEMTEMPERATURE TO REMOVE HEAT FROM LIPID-RICH REGIONS”;

U.S. Patent Publication No. 2009/0018627 entitled “SECURE SYSTEM FORREMOVING HEAT FROM LIPID-RICH REGIONS”;

U.S. Patent Publication No. 2009/0018626 entitled “USER INTERFACES FOR ASYSTEM THAT REMOVES HEAT FROM LIPID-RICH REGIONS”;

U.S. Pat. No. 6,041,787 entitled “USE OF CRYOPROTECTIVE AGENT COMPOUNDSDURING CRYOSURGERY”;

U.S. Pat. No. 8,285,390 entitled “MONITORING THE COOLING OF SUBCUTANEOUSLIPID-RICH CELLS, SUCH AS THE COOLING OF ADIPOSE TISSUE”;

U.S. Provisional Patent Application Ser. No. 60/941,567 entitled“METHODS, APPARATUSES AND SYSTEMS FOR COOLING THE SKIN AND SUBCUTANEOUSTISSUE”;

U.S. Pat. No. 8,275,442 entitled “TREATMENT PLANNING SYSTEMS AND METHODSFOR BODY CONTOURING APPLICATIONS”;

U.S. patent application Ser. No. 12/275,002 entitled “APPARATUS WITHHYDROPHILIC RESERVOIRS FOR COOLING SUBCUTANEOUS LIPID-RICH CELLS”;

U.S. patent application Ser. No. 12/275,014 entitled “APPARATUS WITHHYDROPHOBIC FILTERS FOR REMOVING HEAT FROM SUBCUTANEOUS LIPID-RICHCELLS”;

U.S. Patent Publication No. 2010/0152824 entitled “SYSTEMS AND METHODSWITH INTERRUPT/RESUME CAPABILITIES FOR COOLING SUBCUTANEOUS LIPID-RICHCELLS”;

U.S. Pat. No. 8,192,474 entitled “TISSUE TREATMENT METHODS”;

U.S. Patent Publication No. 2010/0280582 entitled “DEVICE, SYSTEM ANDMETHOD FOR REMOVING HEAT FROM SUBCUTANEOUS LIPID-RICH CELLS”;

U.S. Patent Publication No. 2012/0022518 entitled “COMBINED MODALITYTREATMENT SYSTEMS, METHODS AND APPARATUS FOR BODY CONTOURINGAPPLICATIONS”;

U.S. Publication No. 2011/0238050 entitled “HOME-USE APPLICATORS FORNON-INVASIVELY REMOVING HEAT FROM SUBCUTANEOUS LIPID-RICH CELLS VIAPHASE CHANGE COOLANTS, AND ASSOCIATED DEVICES, SYSTEMS AND METHODS”;

U.S. Publication No. 2011/0238051 entitled “HOME-USE APPLICATORS FORNON-INVASIVELY REMOVING HEAT FROM SUBCUTANEOUS LIPID-RICH CELLS VIAPHASE CHANGE COOLANTS, AND ASSOCIATED DEVICES, SYSTEMS AND METHODS”;

U.S. Publication No. 2012/0239123 entitled “DEVICES, APPLICATION SYSTEMSAND METHODS WITH LOCALIZED HEAT FLUX ZONES FOR REMOVING HEAT FROMSUBCUTANEOUS LIPID-RICH CELLS”;

U.S. patent application Ser. No. 13/830,413 entitled “MULTI-MODALITYTREATMENT SYSTEMS, METHODS AND APPARATUS FOR ALTERING SUBCUTANEOUSLIPID-RICH TISSUE”; and

U.S. patent application Ser. No. 13/830,027 entitled “TREATMENT SYSTEMSWITH FLUID MIXING SYSTEMS AND FLUID-COOLED APPLICATORS AND METHODS OFUSING THE SAME”.

TECHNICAL FIELD

The present disclosure relates generally to treatment devices, methods,and apparatuses for affecting targeted tissue. In particular, severalembodiments are directed to treatment systems, methods, and apparatusesfor improving the appearance of skin or for providing for other patienttreatments.

BACKGROUND

Rhytide (e.g., wrinkles) can affect the appearance of skin on the faceand other areas of the body and may be an indicator of age. For example,wrinkles may be present around the eyes, mouth, forehead, neck, hands,etc. As the skin naturally ages, cell division reduces, skin loosens,and skin sags. Age-related wrinkling of the skin can be promoted and/orexacerbated by habitual facial expressions or sleeping patterns, as wellas poor hydration. Exposure to ultraviolet radiation and tobacco smokecan accelerate the skin's aging process and result in prematurewrinkling. Wrinkles, loose sagging skin, poor skin tone or texture, andother skin abnormalities are often considered to be visually unappealingand have proved to be difficult and vexing problems to treat, althoughthe demand for effective treatments has been and remains quite high. Aneed exists for more effective treatments of these conditions and otherconditions. Accordingly, it is an objective of various embodiments ofthe present invention to address these and other needs.

BRIEF DESCRIPTION OF THE DRAWINGS

In the drawings, identical reference numbers identify similar elementsor acts.

FIG. 1A is a schematic cross-sectional view of tissue with anundesirable appearance.

FIG. 1B is a schematic cross-sectional view of the tissue in FIG. 1Awith an improved appearance. An applicator is in thermal contact withthe surface of the skin.

FIG. 2 is a partially schematic isometric view of a treatment system forimproving the appearance of facial skin in accordance with an embodimentof the disclosure.

FIGS. 3 to 5B are flow diagrams illustrating methods for improving theappearance of skin in accordance with embodiments of the technology.

FIG. 6 is a partially schematic isometric view of a treatment systemtreating tissue located along a subject's torso in accordance with anembodiment of the disclosure.

FIG. 7 is a partial cross-sectional view illustrating a treatment devicein accordance with embodiments of the technology.

FIGS. 8A to 8C are schematic cross-sectional views illustratingtreatment devices in accordance with embodiments of the technology.

FIG. 9 is a partial cross-sectional view illustrating a vacuum treatmentdevice in accordance with another embodiment of the technology.

FIG. 10 is a schematic block diagram illustrating computing systemsoftware modules and subcomponents of a computing device suitable to beused in treatment systems in accordance with an embodiment of thetechnology.

DETAILED DESCRIPTION A. Overview

The present disclosure describes treatment systems and methods forimproving the appearance of tissue and other treatments. Several of thedetails set forth below are provided to describe the following examplesand methods in a manner sufficient to enable a person skilled in therelevant art to practice, make and use them. Several of the details andadvantages described below, however, may not be necessary to practicecertain examples and methods of the technology. Additionally, thetechnology may include other examples and methods that are within thescope of the technology but are not described in detail.

Reference throughout this specification to “one example,” “an example,”“one embodiment,” or “an embodiment” means that a particular feature,structure, or characteristic described in connection with the example isincluded in at least one example of the present technology. Thus, theoccurrences of the phrases “in one example,” “in an example,” “oneembodiment,” or “an embodiment” in various places throughout thisspecification are not necessarily all referring to the same example. Theheadings provided herein are for convenience only and are not intendedto limit or interpret the scope or meaning of the technology.

At least some embodiments are directed to reducing or eliminatingwrinkles, loose skin, sagging skin, poor skin tone or texture, and otherskin irregularities often considered to be cosmetically unappealing.Some embodiments are directed to skin tightening and/or improving theappearance of cellulite. As used herein, the term “improving theappearance of skin” is intended to include any combination of skintightening, improving skin tone or texture, thickening of the skin,elimination or reducing fine lines and wrinkles or deeper wrinkles,increasing skin smoothness, improving the appearance of cellulite, orother similar effects. What is not included in the term is treating theskin to such an extent as to cause hyperpigmentation (skin darkening)and/or hypopigmentation (skin lightening) either immediately after thetreatment or hours or a day or days or weeks thereafter. Treatmentsystems disclosed herein can improve skin appearance by causing skintightening, thickening of tissue (e.g., thickening of the epidermis,dermis, and/or subcutaneous tissue), and/or inducing a cold shockresponse at the cellular level so as to improve skin tone, skin texture,and/or skin smoothness. In one embodiment, a treatment system has anapplicator configured to be applied to a subject's face to treatwrinkles around the eyes, mouth, forehead, etc. The applicator can coolfacial tissue to reduce the number of visible wrinkles, reduce the sizeof wrinkles (e.g., depths, lengths, etc.), or the like. Conformable orcontoured applicators can be applied to highly contoured regions aroundthe eyes to reduce or eliminate, for example, crow's feet wrinkles.Treatment systems can also have applicators configured to be applied toother locations along the subject's body. The shape, configuration,mechanical properties, and cooling capabilities of the applicators canbe selected based on the tissue characteristics at the treatment site.

Various aspects of the technology are directed to non-invasiveapplicators that cool the epidermis, dermis, and/or other tissue for aperiod of time selected to localize thermal effects in targeted tissuewhile preventing thermal effects in deeper non-targeted tissue.Oftentimes, but not always, target tissue can be intermediate (notsurface and not deep) tissue. For example, when treating the face, it isoften undesirable to injure the subcutaneous layer beneath the skin,which acts as a support layer for the skin. Additionally, when treatingthe face and other body areas, it is desirable to minimize or controlinjury to the epidermis. In an extreme case, if the epidermis is overlyfrozen, hyperpigmentation (skin darkening) or hypopigmentation (skinlightening) can result, which is often undesirable. At least someembodiments are methods and apparatuses for non-invasively coolingrelatively shallow tissue located along the face, neck, hands, hips,buttock, thighs, etc. Targeted tissue be cooled to a temperature equalto or below about −40° C., −35° C., −30° C., −25° C., −20° C., −10° C.,or −5° C. for a treatment period equal to or longer than 1 second, 2seconds, 3 seconds, 5 seconds, 30 seconds, 1 minute, a few minutes, orthe like. In some embodiments, targeted epidermal and/or dermal tissuecan be cooled to a temperature between about −40° C. and about 0° C.,between about −35° C. and about 0° C., between about −30° C. and about0° C., between about −25° C. and about 0° C., or between about −20° C.and about 0° C. In some embodiments, the treatment period can be exceedabout 1 minute, 5 minutes, or 20 minutes, or other periods of timeselected based on the treatment to be performed. In some embodiments,the treatment period can be shorter than about 1 minute, 5 minutes, 10minutes, 20 minutes, 30 minutes, or 1 hour. In some procedures, thesurface of the patient's skin is cooled to a temperature equal to orgreater than about −40° C., −35° C., −30° C. −25° C., −20° C., −10° C.,−5° C., or 0° C. Non-targeted tissue may be subcutaneous adipose tissue,epidermal tissue, or other non-targeted tissue that remains at a highertemperature or is otherwise protected, such as by use of one or morecryoprotectants.

In some embodiments, a thermoelectric applicator can cool the patient'sskin to produce a cooling zone in the epidermal and/or dermal layers. Assuch, cooling can be localized in the epidermis and/or dermis. In someexamples, the cooling zone can be at a maximum depth equal to or lessthan about 2.5 mm. In one procedure, a central region of the coolingzone (e.g., a zone where the most tissue injury is created) can be at amaximum depth of about 0.25 mm to about 1 mm, about 0.25 mm to about 1.5mm, about 0.25 mm to about 2 mm, about 0.5 mm to about 1.5 mm, about 0.5mm to about 2 mm, about 0.5 mm to about 2.5 mm, or about 0.5 mm to about3 mm. In some procedures, the depth of the cooling zone and depth of themost significant tissue injury can be at a equal to or less than about 1mm, 1.5 mm, 2 mm, 2.5 mm, or 3 mm. In some procedures for treating areaswith thin skin (e.g., facial skin around the eyes), the cooling zone canbe located at a depth equal to or less than about 1 mm, 0.25 mm, 0.5 mm,1 mm, or 1.5 mm.

Various aspects of the technology are directed to improving theappearance of skin by cooling a surface of a patient's skin to produceat least a cooling event (e.g., a partial freeze event, total freezeevent, etc.). The cooling event can be detected, and a cooling devicecan be controlled to continue cooling the patient's skin so as tomaintain a frozen state of targeted tissue for a desired period of time.In one procedure, the tissue can be kept in a partially or totallyfrozen state for longer than about, for example, about 1 second, 5seconds, 10 seconds, 20 seconds, 30 seconds, 1 minute, several minutes,or other time period selected to reduce or limit frostbite or necrosis.

In certain embodiments, methods for affecting skin of a human subject'sbody include positioning an applicator of a cooling apparatus on thesubject and removing heat from a treatment site to affect the appearanceof the subject's skin without causing an appreciable reduction ofsubcutaneous adipose tissue. A sufficient amount of thermal energy canbe removed from the site so as to reduce wrinkles by, for example,reducing the number of visible wrinkles and/or sizes of the wrinkles. Inother embodiments, a sufficient amount of thermal energy is removed fromthe treatment site so as to tighten skin at the treatment site, or infurther embodiments, to alter the tissue between a surface of the skinand subcutaneous lipid-rich cells of the subject's body. In a furtherembodiment, tissue is cooled to induce fibrosis that increases thefirmness of tissue at the treatment site. Fibrosis can be induced in theepidermis, dermis, and/or subcutaneous tissue. Vacuum applicators canstretch or otherwise mechanically alter skin to increase damage andfibrosis in the skin.

At least some aspects of the technology are directed to treatmentmethods for affecting a target region of a human subject's body to alteran appearance of a treatment site by removing heat using a coolingapparatus to alter at least one of skin tightness, smoothness, or skinsurface irregularities. The methods can include removing a sufficientamount of heat to produce fibrosis that alters the subject's skin. Incertain embodiments, the fibrosis increases the tightness of the skinand/or increases the smoothness of the surface of the skin. Otherembodiments of the technology are directed to methods of cooling tissueusing a cooling apparatus to produce a cold shock response for affectingproteins that alter the appearance of the subject's skin. The proteinscan be heat shock proteins, cold shock proteins, and/or stress responseproteins. In one embodiment, tissue can be cooled to a temperature forincreasing a protein synthesis rate of one or more of the proteins.

At least some embodiments of the technology are directed to freezingskin to induce injury to the skin. An applicator can be placed at atreatment site on the subject and can remove heat from the subject'sskin to controllably freeze the skin to control the freeze injury (ortrauma) to the skin. The freeze injury can improve tissue appearance by,for example, tightening of the skin, thickening of the skin, and/orinducing a cold shock response at the cellular level. In someprocedures, most of the skin located between the applicator andsubcutaneous tissue can experience at least partial freezing. With orwithout freezing, at least some embodiments of the technology aredirected to controlling the cooling device or providing other means forsufficiently protecting the epidermis from injury to an extent thatcauses hyperpigmentation (skin darkening) or hypopigmentation (skinlightening). The other means can include heating the epidermis to anon-freezing temperature while deeper tissue remains cold to induceinjury thereto, and/or applying a cryoprotectant to a surface of theskin to provide freeze protection to the epidermis while allowing deepertissue to be more affected by the cooling/cold treatment.

In further embodiments of the technology, damage to tissue (e.g., dermisand/or subcutaneous tissue) can be reduced or eliminated by applying asubstance to the subject's skin. In other embodiments, tissue damage canbe limited by applying energy to non-targeted tissue while cooling thetreatment site. For example, electromagnetic energy, infrared energy,microwave energy, radiofrequency energy, ultrasound energy, electricalenergy (e.g., AC or DC electric fields), and/or light can be deliveredto the subject's skin to supply energy thereto. In certain arrangements,the applied energy can inhibit the reduction of subcutaneous lipid-richcells while the treatment site is cooled by the applicator.

Some aspects of the technology are directed to treatment methods foraffecting tissue of a human subject's body by cooling tissue to producea freeze event that affects at least one of skin tone, thickness of thetissue layers (e.g., dermal layer and/or epidermal layer), and/or tissueelasticity. In certain embodiments, the method also includes inhibitingdamage to non-targeted tissue of the subject's skin while producing thefreeze event. The freeze event can include injury to at least some ofthe subject's skin (e.g., epidermis, dermis, etc.), subcutaneous adiposetissue, or other targeted tissue.

Devices and systems that enable target tissue supercooling are alsodescribed. A freezing point of a material is most reliably ascertainedby warming frozen material slowly and measuring a temperature at whichmelting begins to occur. This temperature is generally not ambiguous ifthe material is slowly warmed. Partial melting will begin to occur atthe freezing/melting point. Conversely, if a non-frozen material iscooled, its freezing/melting point is harder to ascertain since it isknown that many materials can simply “supercool,” that is they can becooled to a bulk temperature below their freezing/melting point andstill remain in a non-frozen state. As used herein, “supercooling,”“supercooled,” “supercool,” etc., refers to a condition in which amaterial is at a temperature below its freezing/melting point but isstill in an unfrozen or mostly unfrozen state.

Tissue can be supercooled by controllably cooling the surface of theskin for altering and reducing adipose tissue, body contouring andaugmentation, treating of acne, treating hyperhidrosis, or othercryotherapy applications. Aspects of the disclosure are further directedto methods and devices that provide protection of non-targeted cells,such as non-lipid-rich cells (e.g., in the dermal and/or epidermal skinlayers), by preventing or limiting freeze damage during dermatologicaland related aesthetic procedures that require sustained exposure to coldtemperatures. For example, treatment systems and devices for performingcryotherapy methods can be configured to control thermal parameters suchthat body fluids within the treatment site are supercooled totemperatures below the freezing point without forming or nucleating icecrystals. The supercooled body fluids can then be intentionallynucleated to damage, reduce, disrupt, or otherwise affect the targetedcells. Nucleation can be induced by delivering an alternating current tothe tissue, applying a nucleating solution onto the surface of the skin(for example one that includes bacteria which initiate nucleation),and/or by creating a mechanical perturbation to the tissue, such as byuse of vibration, ultrasound energy, etc.

Some of the embodiments disclosed herein can be for cosmeticallybeneficial alterations of a variety of body regions. As such, sometreatment procedures may be for the sole purpose of altering the bodyregion to conform to a cosmetically desirable look, feel, size, shape orother desirable cosmetic characteristic or feature. Accordingly, atleast some embodiments of the cosmetic procedures can be performedwithout providing any, or in another embodiment, providing minimaltherapeutic effect. For example, some treatment procedures may bedirected to treatment goals that do not include restoration of health,physical integrity, or the physical well-being of a subject. In otherembodiments, however, the cosmetically desirable treatments may havetherapeutic outcomes (whether intended or not), such as, psychologicalbenefits, alteration of body hormones levels (by the reduction ofadipose tissue), etc. The cosmetic methods can target regions of asubject's skin to change a subject's appearance. In another embodiment,the methods can target skin irregularities, wrinkles, sebaceous glandsto treat acne, sweat glands to treat hyperhidrosis, hair follicles toinjure and remove hair, or other targeted cells to change a subject'sappearance or address a therapeutic condition.

B. Treatment Sites

FIG. 1A is a schematic cross-sectional view of tissue with skin 10having wrinkles 20 (e.g., folds, ridges, or creases) that may belocated, for example, along the face, legs (e.g., thighs, buttock,etc.), or other locations. The dimensions (e.g., depths, lengths, etc.)of the wrinkles 20 can vary by body location and typically increase overtime. Wrinkles 20 typically affect the epidermis 14 and dermis 12 layersof the skin; however, the subdermal adipose and connective tissue canalso play a role in the appearance of skin irregularities. For example,loss of adipose or fat cells 18 and/or weakened connective tissue 22 inthe subcutaneous layers (e.g., subdermal tissue 16) can increase theappearance of wrinkles 20 in the skin 10.

FIG. 1B is a schematic cross-sectional view of the skin 10 of thesubject in FIG. 1A with improved appearance. An illustrated treatmentdevice in the form of a thermoelectric applicator 104 (“applicator 104”)has affected tissue (e.g., skin 10, epidermis 14, dermis 12, or othertargeted tissue) to reduce or eliminate the wrinkles, improve skin toneand/or texture, increase skin smoothness, and/or improve the appearanceof cellulite. The applicator 104 can perform different cryotherapyprocedures designed to make the skin 10 substantially free of visibleirregularities.

In one example, a heat-exchanging surface 19 of the applicator 104 canbe in thermal contact with a surface of the skin 10. A cooling device103 of the applicator 104 can cool a treatment site 15 and affect tissueat a cooling zone 21 (shown in phantom line). A central region 17 of thecooling zone 21 can be at a maximum depth of, for example, about 0.25 mmto about 2 mm, about 0.25 mm to about 1 mm, about 0.5 mm to about 1 mm,or about 0.5 mm to about 2 mm. The depth of the cooling zone 21 can beselected to avoid injuring deeper subcutaneous tissue (e.g., subdermaltissue 16). In one procedure, the cooling zone 21 comprises mostlyepidermal tissue. In another procedure, the cooling device 103 cools andaffects tissue in the cooling zone 21′ (shown in dashed-dot line) whichcomprises mostly epidermal and dermal tissue. Adjacent tissue (e.g.,subcutaneous tissue) may also be cooled but can be at a sufficientlyhigh temperature to avoid thermal injury. In some procedures, thecooling zone 21′ can comprise most of the tissue located directlybetween the cooled heat-exchanging surface 19 and the subcutaneoustissue (e.g., dermal tissue 16). For example, at least about 60%, 70%,80%, 90%, or 95% of the tissue directly between the heat-exchangingsurface 19 and the subcutaneous tissue can be located within the coolingzone 21′.

C. Cryotherapy

FIG. 2 and the following discussion provide a general description of anexample of a suitable non-invasive treatment system 100 in which aspectsof the technology can be implemented. The treatment system 100 can be atemperature-controlled cooling apparatus for cooling tissue at atargeted treatment site to perform cryotherapy. Tissue characteristicsaffected by cryotherapy can include, without limitation, tissuestrength, tissue elasticity, cell size, cell number, and/or tissue layerthickness. For example, the treatment system 100 can cool the epidermis,dermis, or other targeted tissue to reduce or eliminate skinirregularities. Non-targeted tissue, such as subdermal tissue, canremain generally unaffected. In one embodiment, cryotherapy can increasethe thicknesses of multiple tissue layers. In one example, cooling canproduce a cold shock response to increase the thicknesses of theepidermis and/or dermis by affecting protein proliferation and othercellular functions. Those skilled in the relevant art will appreciatethat other examples of the disclosure can be practiced with othertreatment systems and treatment protocols, including invasive, minimallyinvasive, and other non-invasive medical treatments.

The applicator 104 is suitable for altering a human subject's skinwithout affecting subcutaneous tissue (e.g., subcutaneous adipose tissueand lipid-rich cells, etc.). The applicator 104 can be suitable forreducing wrinkles (e.g., wrinkles 20 of FIG. 1A), loose skin, saggingskin, or other skin surface irregularities by cooling the skin withoutpermanently altering cells of non-targeted tissue (e.g., deep dermaltissue, subdermal tissue, etc.). Without being bound by theory, theeffect of cooling selected cells (e.g., cells of the skin, layers ofepidermis, etc.) is believed to result in, for example, proteinalteration (e.g., synthesis of heat shock proteins, stress proteins,etc.), cell size alteration, cell division, wound remodeling (e.g.,thickening of the epidermis, contraction of the epidermis, etc.),fibrosis, and so forth. By cooling the skin to a sufficient lowtemperature, target cells that contribute to the presence of undesiredfeatures can be selectively affected while non-targeted tissue can beunaffected.

The applicator 104 can be used to perform a wide range of differentcryotherapy procedures. One cryotherapy procedure involves at leastpartially or totally freezing tissue to form crystals that altertargeted cells to cause skin tightening, skin thickening, fibrosis, etc.without destroying a significant amount of cells in the skin. To avoiddestroying skin cells, the surface of the patient's skin can be cooledto temperatures no lower than, for example, 40° C. for a duration shortenough to avoid, for example, excessive ice formation, permanent thermaldamage, or significant hyperpigmentation or hypopigmentation (includinglong-lasting or permanent hyperpigmentation or hypopigmentation). Inanother embodiment, destruction of skin cells can be avoided by applyingheat to the surface of the patient's skin to heat the skin cells abovetheir freezing temperature. The patient's skin can be warmed to at leastabout −30° C., −25° C., −20° C., −15° C., −10° C., 0° C., 10° C., 20°C., 30° C., or other temperature sufficient to avoid, for example,excessive ice formation, permanent thermal damage, or significanthyperpigmentation or hypopigmentation of the non-targeted and/orepidermal tissue. In some treatments, skin can be cooled to producepartial freeze events that cause apoptotic damage to skin tissue withoutcausing significant damage to adjacent subcutaneous tissue. Apoptosis,also referred to as “programmed cell death”, of the skin tissue can be agenetically-induced death mechanism by which cells slowly self-destructwithout incurring damage to surrounding tissues. Other cryotherapyprocedures may cause non-apoptotic responses.

In some tissue-freezing procedures, the applicator 104 can controllablyfreeze tissue and can optionally detect the freeze event (or otherevent). After detecting the freeze event, the applicator 104 canperiodically or continuously remove heat from the target tissue to keepa volume of target tissue frozen or partially frozen for a suitablelength of time to elicit a desired response. The detected freeze eventcan be a partial freeze event, a complete freeze event, etc. In someembodiments, the controlled freezing causes tightening of the skin,thickening of the skin, and/or a cold shock response at the cellularlevel in the skin. In one tissue-freezing treatment, the applicator 104can produce a partial or total freeze event that includes, withoutlimitation, partial or full thickness freezing of the patient's skin fora relatively short time limit to avoid cooling the adjacent subcutaneoustissue to a low enough temperature for subcutaneous cell death or undueinjury to the subcutaneous layer. The freezing process can includeforming ice crystals in intracellular and/or extracellular fluids, andthe ice crystals can be small enough to avoid disrupting membranes so asto prevent significant permanent tissue damage, such as necrosis. Somepartial freeze events can include freezing mostly extracellular materialwithout freezing a substantial amount of intercellular material. Inother procedures, partial freeze events can include freezing mostlyintercellular material without freezing a substantial amount ofextracellular material. The frozen target tissue can remain in thefrozen state long enough to affect the target tissue but short enough toavoid damaging non-targeted tissue. For example, the duration of thefreeze event can be shorter than about 20 seconds, 30 seconds, or 45seconds or about 1, 2, 3, 4, 5 or 10 minutes. The frozen tissue can bethawed to prevent necrosis and, in some embodiments, can be thawedwithin about 20 seconds, 30 seconds, or 45 seconds or about 1, 2, 3, 4,5, or 10 minutes after initiation of the freeze event.

In several embodiments, tissue can be cooled to induce cold shockcellular responses in the region of the subject being treated are adesirable outcome for beneficially alter (e.g., smoothing and/ortightening) the skin. Without being bound by theory, it is believed thatexposure to cold induces a stress response cascade in the interrogatedcells that results in the immediate synthesis of cytoprotective genes.Among these are genes that code for heat shock proteins and/or chaperoneproteins involved in protein folding. Heat shock proteins can help altera cell's phenotype by either impeding, protecting or promoting proteinfunction both during the acute response to stress as well as tosubsequent stresses. Cold shock proteins (e.g., cold-inducibleRNA-binding protein (CIRP) that may have roles in cellular proliferationand inflammation) have also been identified in mammalian cells.Induction of cold shock cellular responses can dramatically change acell's proteome to promote cellular survival under environmentalinterrogation and/or following cold-induced tissue injury. It has beenobserved in mammalian cells that cold stress can alter the lipidcomposition of the cellular membranes, as well as change rates ofprotein synthesis and cell proliferation. Without being bound by theory,the selective effect of cooling on target cells (e.g., epidermal and/ordermal cells) is believed to result in, for example, changes in cellularmetabolism, proliferation, survivability, wound healing, woundcontraction and other cellular responses that can improve tissuecharacteristics at the treatment site.

The mechanisms of cold-induced tissue injury in cryotherapy can alsoinvolve direct cellular injury (e.g., damage to the cellular machinery)and/or vascular injury. For example, cell injury can be controlled byadjusting thermal parameters, including (1) cooling rate, (2) end (orminimum) temperature, (3) time held at the minimum temperature (or holdtime), (4) temperature profile, and (5) thawing rate. In one example,increasing the hold time can allow the intracellular compartments toequilibrate with the extracellular space, thereby increasing cellulardehydration. Another mechanism of cold-induced injury is cold and/orfreeze-stimulated immunologic injury. Without being bound by theory, itis believed that after cryotherapy, the immune system of the host issensitized to the disrupted tissue (e.g., lethally damaged tissue,undamaged tissue, or sublethally injured tissue), which can besubsequently destroyed by the immune system.

During an inflammatory phase of healing following cold-induced injury,platelets are among the first cells to appear at the treatment site.Platelets release platelet derived growth factor (PDGF), whichupregulates soluble fibrinogen production. Fibrinogen is converted toinsoluble strands of fibrin which form a matrix for the influx ofmonocytes and fibroblasts. During a proliferative phase of healing,cellular activity promotes epithelialization and fibroplasia.Fibronectin, produced initially from plasma, promotes epidermalmigration by providing its own lattice. In freeze wounds, basalkeratinocytes secrete collagenase-1 when in contact with fibrillarcollagen, and collagenase-1 disrupts attachment to fibrillar collagenwhich allows for continued migration of keratinocytes into the treatmentsite. It is during the proliferative phase that a healing processfollowing injury can result in a thicker epidermal layer with increasedcellular activity.

In additional embodiments, induction of fibrosis (e.g., the formation offibrous connective tissue) in the region of the subject being treated isa desirable outcome for beneficially altering the skin. For example,fibrosis can increase the amount of connective tissue in a desiredtissue layer (e.g., epidermis, dermis, and/or subcutaneous tissue) toincrease a firmness of the tissue. In some embodiments, increasedfirmness of the tissue can increase the tightness and/or the smoothnessof the surface of the skin. Without being bound by theory, coolingtemperatures can result in inflammation of the interrogated tissue.Immune cells, such as macrophages, release transforming growth factorbeta (TGF-β) which stimulates the proliferation and activation offibroblast cells. Migrating and activated fibroblast cells depositconnective tissue, including collagen and glycosaminoglycans that canthicken and/or strengthen the affected tissue. Such thickening and/orfirming of the affected tissue can beneficially alter skincharacteristics by reducing the appearance of wrinkles, fine lines,loose skin, etc.

The system 100 can also perform treatments to affect subcutaneous tissueby cooling the subject's skin for a period of time long enough so thatlipid-rich cells in a subcutaneous layer are substantially affected.This can be desired particularly when treating non-facial areas, such asthe thighs, arms, abdomen etc., where a skin tightening effect isdesired as well as a volumetric reduction, which is aided by alteringsubcutaneous lipid rich cells. The term “subcutaneous tissue” meanstissue lying beneath the dermis and includes subcutaneous fat, oradipose tissue, which is composed primarily of lipid-rich cells, oradipocytes. It is believed that shallow tissue can be cooled to improveskin appearance while also cooling subcutaneous tissue to cause, forexample, apoptosis. Apoptosis of subcutaneous lipid-rich cells may be adesirable outcome for beneficially altering (e.g., sculpting and/orreducing) adipose tissue that may contribute to an undesirableappearance. Apoptosis of subcutaneous lipid-rich cells can involveordered series of biochemical events that induce cells tomorphologically change. These changes include cellular blebbing, loss ofcell membrane asymmetry and attachment, cell shrinkage, chromatincondensation, and chromosomal DNA fragmentation. Injury via an externalstimulus, such as cold exposure, is one mechanism that can induceapoptosis in cells. Nagle, W. A., Soloff, B. L., Moss, A. J. Jr., Henle,K. J. “Cultured Chinese Hamster Cells Undergo Apoptosis After Exposureto Cold but Nonfreezing Temperatures” Cryobiology 27, 439-451 (1990).One aspect of apoptosis, in contrast to cellular necrosis (a traumaticform of cell death causing, and sometimes induced by, localinflammation), is that apoptotic cells express and display phagocyticmarkers on the surface of the cell membrane, thus marking the cells forphagocytosis by, for example, macrophages. As a result, phagocytes canengulf and remove the dying cells (e.g., the lipid-rich cells) withouteliciting an immune response.

Without being bound by theory, one mechanism of apoptotic lipid-richcell death by cooling is believed to involve localized crystallizationof lipids within the adipocytes at temperatures that may or may notinduce crystallization in non-lipid-rich cells. The crystallized lipidsmay selectively injure these cells, inducing apoptosis (and may alsoinduce necrotic death if the crystallized lipids damage or rupture thebilayer lipid membrane of the adipocyte). Another mechanism of injuryinvolves the lipid phase transition of those lipids within the cell'sbilayer lipid membrane, which results in membrane disruption, therebyinducing apoptosis. This mechanism is well documented for many celltypes and may be active when adipocytes, or lipid-rich cells, arecooled. Mazur, P., “Cryobiology: the Freezing of Biological Systems”Science, 68: 939-949 (1970); Quinn, P. J., “A Lipid Phase SeparationModel of Low Temperature Damage to Biological Membranes” Cryobiology,22: 128-147 (1985); Rubinsky, B., “Principles of Low TemperaturePreservation” Heart Failure Reviews, 8, 277-284 (2003). Other possiblemechanisms of adipocyte damage, described in U.S. Pat. No. 8,192,474,relates to ischemia/reperfusion injury that may occur under certainconditions when such cells are cooled as described herein. For instance,during treatment by cooling as described herein, targeted adipose tissuemay experience a restriction in blood supply and thus be starved ofoxygen due to isolation while pulled into, e.g., a vacuum cup, or simplyas a result of the cooling which may affect vasoconstriction in thecooled tissue. In addition to the ischemic damage caused by oxygenstarvation and the build-up of metabolic waste products in the tissueduring the period of restricted blood flow, restoration of blood flowafter cooling treatment may additionally produce reperfusion injury tothe adipocytes due to inflammation and oxidative damage that is known tooccur when oxygenated blood is restored to tissue that has undergone aperiod of ischemia. This type of injury may be accelerated by exposingthe adipocytes to an energy source (via, e.g., electromagnetic, thermal,electrical, chemical, mechanical, acoustic or other means) or otherwiseincreasing the blood flow rate in connection with or after coolingtreatment as described herein. Increasing vasoconstriction in suchadipose tissue by, e.g., various mechanical means (e.g., application ofpressure or massage), chemical means or certain cooling conditions, aswell as the local introduction of oxygen radical-forming compounds tostimulate inflammation and/or leukocyte activity in adipose tissue mayalso contribute to accelerating injury to such cells. Other yet-to-beunderstood mechanisms of injury may also exist.

In addition to the apoptotic mechanisms involved in lipid-rich celldeath, local cold exposure may induce lipolysis (i.e., fat metabolism)of lipid-rich cells. For example, cold stress has been shown to enhancerates of lipolysis from that observed under normal conditions whichserves to further increase the volumetric reduction of subcutaneouslipid-rich cells. Vallerand, A. L., Zamecnik. J., Jones, P. J. H.,Jacobs, I. “Cold Stress Increases Lipolysis, FFA Ra and TG/FFA Cyclingin Humans” Aviation, Space and Environmental Medicine 70, 42-50 (1999).

Without being bound by theory, the effect of cooling on lipid-rich cellsis believed to result in, for example, membrane disruption, shrinkage,disabling, destroying, removing, killing, or another method oflipid-rich cell alteration. For example, when cooling the subcutaneoustissues to a temperature lower than 37° C., subcutaneous lipid-richcells can selectively be affected. In general, the cells in theepidermis and dermis of the subject 101 have lower amounts of lipidscompared to the underlying lipid-rich cells forming the subcutaneoustissues. Since lipid-rich cells are more sensitive to cold-induceddamage than non-lipid-rich epidermal or dermal cells, it is possible touse non-invasive or minimally invasive cooling to destroy lipid-richcells without destroying the overlying skin cells. In some embodiments,lipid-rich cells are destroyed while the appearance of overlying skin isimproved.

Deep hypodermal fat cells are more easily damaged by low temperaturesthan the overlying dermal and epidermal layers of skin, and as such,thermal conduction can be used to cool the desired layers of skin to atemperature above the freezing point of water, but below the freezingpoint of fat. It is believed that the temperatures can be controlled tomanage damage in the epidermis and/or dermis via, for example,intracellular and/or extracellular ice formation. Excessive iceformation may rupture the cell wall and may also form sharp crystalsthat locally pierce the cell wall as well as vital internal organelles.Ice crystal initiation and growth can be managed to avoid cell death inthe skin. When extracellular water freezes to form ice, the remainingextracellular fluid becomes progressively more concentrated withsolutes. The high solute concentration of the extracellular fluid maycause intracellular fluid to be driven through the semi-permeablecellular wall by osmosis resulting in cell dehydration. The applicator104 can reduce the temperature of the deep lipid-rich cells such thatthe deep lipid rich cells are destroyed while the temperature of theupper and surface skin cells are maintained at a high enough temperatureto produce non-destructive freeze events in the skin. Cryoprotectantsand/or thermal cycling can prevent destructive freeze events in the skinand limit injury to the skin cells.

D. Treatment Systems and Methods of Treatment

FIG. 2 is a partially schematic isometric view of the non-invasivelytreatment system 100 for performing cryotherapy procedures disclosedherein. The term “treatment system”, as used generally herein, refers tocosmetic or medical treatment systems. The components of the treatmentsystem 100 can be selected and implemented in various embodiments toapply selected treatment profiles to the subject 101 (e.g., a human oran animal) for improving the appearance of the treatment site. Thetreatment system 100 can include a treatment unit or tower 102(“treatment tower 102”) connected to the applicator 104 by supply andreturn fluid lines 108 a-b and power-lines 109 a-b.

The applicator 104 can have one or more cooling devices powered byelectrical energy delivered via the power-lines 109 a-b. A control line116 can provide communication between electrical components of theapplicator 104 and a controller 114 of the treatment tower 102. Thecooling devices of the applicator 104 can be cooled using coolant thatflows between the applicator 104 and the treatment tower 102 via thesupply and return fluid lines 108 a-b. In one example, the applicator104 has a cooling device (e.g., cooling device 103 of FIG. 1B) with oneor more thermoelectric cooling elements and fluid channels through whichthe coolant flows to cool the thermoelectric cooling elements. Thethermoelectric cooling elements can include heat-exchanging plates,Peltier devices, or the like. In one embodiment, the applicator 104 canbe a non-thermoelectric device that is heated/cooled using only coolant.The applicator 104 can include sensors configured to measure tissueimpedance, treatment application force, and/or tissue contact. Asdescribed herein, sensors can be used to monitor tissue and, in someembodiments, detect freeze events. Applicators configured to be appliedto facial tissue can have pressure sensors to monitor applied pressuresto maintain a desired level of comfort. The number and types of sensorscan be selected based on the treatment to be performed.

The treatment tower 102 can include a chiller unit or module 106(“chiller unit 106”) capable of removing heat from the coolant. Thechiller unit 106 can include one or more refrigeration units,thermoelectric chillers, or any other cooling devices and, in oneembodiment, includes a fluid chamber configured to house the coolantthat is delivered to the applicator 104 via the fluid lines 108 a-b. Insome procedures, the chiller unit 106 can circulate warm coolant to theapplicator 104 during periods of warming. In certain procedures, thechiller unit 106 can alternatingly provide heated and chilled coolant.The circulating coolant can include water, glycol, synthetic heattransfer fluid, oil, a refrigerant, or any other suitable heatconducting fluid. Alternatively, a municipal water supply (e.g., tapwater) can be used in place of or in conjunction with the treatmenttower 102. The fluid lines 108 a-b can be hoses or other conduits madeof polyethylene, polyvinyl chloride, polyurethane, and/or othermaterials that can accommodate the particular coolant. One skilled inthe art will recognize that there are a number of other coolingtechnologies that could be used such that the treatment unit, chillerunit, and/or applicator(s) need not be limited to those describedherein. Additional features, components, and operation of the treatmenttower 102 are discussed in connection with FIG. 6.

FIG. 2 shows the applicator 104 positioned to treat crow's feet wrinklesnear the patient's right eye. Feedback data from sensors of theapplicator 104 can be collected in real-time because real-timeprocessing of such feedback data can help correctly and efficaciouslyadminister treatment. In one example, real-time data processing is usedto detect freeze events and to control the applicator 104 to continuecooling the patient's skin after the partial or total freeze event isdetected. Tissue can be monitored to keep the tissue in the frozen state(e.g., at least partially or totally frozen state) for a period of time.The period of time can be selected by the treatment tower 102 or anoperator and can be longer than about, for example, 10 seconds, 30seconds, 1 minute, or a few minutes. Other periods of time can beselected if needed or desired. The applicator 104 can include sensorsconfigured to measure tissue impedance, force/pressure applied to thesubject 101, optical characteristics of tissue, and/or tissue contacttemperatures. As described herein, sensors can be used to monitor tissueand, in some embodiments, to detect freeze events. The number and typesof sensors can be selected based on the treatment to be performed.

The applicator 104 can be used at other treatment sites and can bereplaced with other applicators. Applicators can be configured to treatidentified portions of the patient's body, such as the face, neck, chin,cheeks, arms, pectoral areas, thighs, calves, buttocks, abdomen, “lovehandles”, back, hands, and so forth. For example, mask applicators canbe used to cover the subject's face. Conformable applicators can beapplied along the face, neck, or other highly contoured regions. By wayof another example, vacuum applicators may be applied at the backregion, and belt applicators can be applied around the thigh region,either with or without massage or vibration as discussed in connectionwith FIG. 9. Exemplary applicators and their configurations usable oradaptable for use with the treatment system 100 variously are describedin, e.g., U.S. Pat. No. 8,834,547 and commonly assigned U.S. Pat. No.7,854,754 and U.S. Patent Publication Nos. 2008/0077201, 2008/0077211,and 2008/0287839, which are incorporated by reference in theirentireties.

In further embodiments, the system 100 of FIG. 2 may also include apatient protection device (not shown) incorporated into or configuredfor use with the applicator 104 that prevents the applicator fromdirectly contacting a patient's skin and thereby reduces the likelihoodof cross-contamination between patients and minimizes cleaningrequirements for the applicator. The patient protection device may alsoinclude or incorporate various storage, computing, and communicationsdevices, such as a radio frequency identification (RFID) component, tomonitor and/or meter use. Exemplary patient protection devices aredescribed in commonly assigned U.S. Patent Publication No. 2008/0077201.

In operation, and upon receiving input to start a treatment protocol,the controller 114 can cycle through each segment of a prescribedtreatment plan. In so doing, power supply 110 and chiller unit 106 canprovide power and coolant to one or more functional components of theapplicator 104, such as thermoelectric coolers (e.g., TEC “zones”), tobegin a cooling cycle and, in some embodiments, activate features ormodes such as vibration, massage, vacuum, etc. The controller 114 canmonitor treatment by receiving temperature readings from temperaturesensors that are part of the applicator 104 or proximate to theapplicator 104, the patient's skin, a patient protection device, etc. Itwill be appreciated that while a target region of the body has beencooled or heated to the target temperature, in actuality that region ofthe body may be close but not equal to the target temperature, e.g.,because of the body's natural heating and cooling variations. Thus,although the system 100 may attempt to heat or cool the tissue to thetarget temperature or to provide a target heat flux, a sensor maymeasure a sufficiently close temperature or heat flux. If the targettemperature has not been reached, power can be increased or decreased tochange heat flux to maintain the target temperature or “set-point”selectively to affect targeted tissue. The system 100 can thus monitorthe treatment site while accurately cooling/heating tissue to performthe methods discussed herein.

FIG. 3 is a flow diagram illustrating a method 140 for improving theappearance of a subject's skin in accordance with embodiments of thedisclosure. An early stage of the method 140 can include coupling aheat-exchanging surface of a treatment device with the surface of thesubject's skin at a target region (block 142). FIG. 1B shows theheat-exchanging surface 19 in the form of an exposed surface of aheat-exchanging plate of the applicator 104. In another embodiment, theheat-exchanging surface 19 can be the surface of an interface layer or adielectric layer. Coupling of the heat-exchanging surfaces to the skincan be facilitated by using restraining means, such as a belt or strap.In other embodiments, a vacuum or suction force can be used topositively couple the treatment device to the patient's skin. In somemethods, a thermally conductive substance can couple the heat-exchangingsurface 19 to the patient's skin and can optionally be a cryoprotectant.Suitable and preferred cryoprotectants are described in commonlyassigned U.S. Patent Publication No. 2007/0255362.

At block 144, heat is removed from tissue for a period of time that mayvary depending on the location of the treatment site and may induce coldshock, freeze tissue, injure tissue, etc. Thermal injuries can inducefibrosis that increases the firmness and/or tone of the tissue. In somecold shock procedures, the subject's skin can be cooled to produce acold shock response which affects proteins, such as heat shock proteins,cold shock proteins, and/or stress response proteins. In someembodiments, the subject's skin can be cooled to a temperature no lowerthan about −40° C., −30° C., −20° C., −10° C. to produce the cold shockresponse. Additionally or alternatively, the treatment site can becooled to a temperature selected to increase a protein synthesis rate ofone or more of the proteins. Some treatment protocols can include two ormore segments each designed to produce cold shocks responses, freezetissue, or injure tissue. For example, a treatment protocol mayalternate between tissue-freeze segments and tissue-thaw segments. Inanother example, one treatment protocol can be designed to reducewrinkles (e.g., age-related wrinkles) via shock proteins and anothertreatment protocol can be designed to tighten loose tissue via fibrosis.Accordingly, different treatment protocols can be used on differentparts of a patient's body. Although the method 140 is described withreference to the treatment system 100 of FIG. 2, the method 140 may alsobe performed using other treatment systems with additional or differentapplicators, hardware, and/or software components.

FIG. 4 is a flow diagram illustrating a method 150 for improving theappearance of skin in accordance with embodiments of the disclosure. Themethod 150 can include coupling a heat-exchanging surface of a treatmentdevice with the surface of the subject's skin at a target region (block152). At block 154, the method 150 includes cooling the subject's skinto affect tissue at the target region. In one embodiment, the skin'ssmoothness, thickness, texture, tone, and/or elasticity is improved. Inone embodiment, the skin is cooled to induce a freeze-related injury,and in another embodiment, the skin is cooled to induce a cold shockresponse.

FIG. 5A is a flow diagram illustrating a method 160 for improving theappearance of skin by producing a freeze event in accordance withembodiments of the disclosure. Generally, a treatment device can beapplied to a subject and can cool a surface of a patient's skin toproduce and detect a freeze event. After detecting the freeze event (orevents), operation of the treatment device can be controlled to keep atleast a portion of the subject's tissue frozen for a sufficient lengthof time to improve the appearance of the skin but not so long as tocreate undue injury to tissue. Details of method 160 are discussedbelow.

At block 162, the treatment device is applied to a subject by placing aheat-exchanging surface in thermal contact with the subject's skin. Insome embodiments, a substance is applied to the subject's skin beforeapplying the treatment device. A substance can be used to (a) providethermal coupling between the subject's skin and cooling devices (e.g.,cooling plates of cooling devices) to improve heat transfertherebetween, (b) selectively protect non-target tissues from freezedamage (e.g., damage due to crystallization), and/or (c) promote freezeevents by increasing nucleation sites. The substance may be a fluid, agel, or a paste and may be hygroscopic, thermally conductive, andbiocompatible. In some embodiments, the substance can be acryoprotectant that reduces or inhibits cell destruction. As usedherein, “cryoprotectant,” “cryoprotectant agent,” and “composition” meansubstances (e.g., compositions, formulations, compounds, etc.) thatassist in preventing freezing of tissue compared to an absence of thesubstances(s). In one embodiment, the cryoprotectant allows, forexample, the treatment device to be pre-cooled prior to being applied tothe subject for more efficient treatment. Further, the cryoprotectantcan also enable the treatment device to be maintained at a desired lowtemperature while preventing ice from forming on a surface (e.g.,heat-exchanging surface), and thus reduces the delay in reapplying thetreatment device to the subject. Yet another aspect of the technology isthat the cryoprotectant may prevent the treatment device from freezingto the skin of the patient or subject. Additionally or alternatively,the cryoprotectant can allow microscopic crystals to form in the tissuebut can limit crystal growth that would cause cell destruction and, insome embodiments, allows for enhanced uptake or absorption and/orretention in target tissue prior to and during the introduction ofcooling.

Some embodiments according to the present technology may use acryoprotectant with a freezing point depressant that can assist inpreventing freeze damage that would destroy cells. Suitablecryoprotectants and processes for implementing cryoprotectants aredescribed in commonly-assigned U.S. Patent Publication No. 2007/0255362.The cryoprotectant may additionally include a thickening agent, a pHbuffer, a humectant, a surfactant, and/or other additives and adjuvantsas described herein. Freezing point depressants may include, forexample, propylene glycol (PG), polyethylene glycol (PEG), dimethylsulfoxide (DMSO), or other suitable alcohol compounds. In a particularembodiment, a cryoprotectant may include about 30% propylene glycol,about 30% glycerin (a humectant), and about 40% ethanol. In anotherembodiment, a cryoprotectant may include about 40% propylene glycol,about 0.8% hydroxyethyl cellulose (a thickening agent), and about 59.2%water. In a further embodiment, a cryoprotectant may include about 50%polypropylene glycol, about 40% glycerin, and about 10% ethanol. Thefreezing point depressant may also include ethanol, propanol,iso-propanol, butanol, and/or other suitable alcohol compounds. Certainfreezing point depressants (e.g., PG, PPG, PEG, etc.) may also be usedto improve spreadability of the cryoprotectant and to providelubrication. The freezing point depressant may lower the freezing pointof body liquids/lipids to about 0° C. to −50° C., about 0° C. to −50°C., or about 0° C. to −30° C. In other embodiments the freezing point ofthe liquids/lipids can be lowered to about −10° C. to about −40° C.,about −10° C. to about −30° C., or to about −10° C. to about −20° C. Incertain embodiments, the freezing point of the liquids/lipids can belowered to a temperature below about 0° C., below about −5° C., belowabout −10° C., below about −12° C., below about −15° C., below about−20° C., below about −30° C., or below about −35° C. For example, thefreezing point depressant may lower the freezing point of theliquids/lipids to a temperature of about −1° C. to about −40° C., about−5° C. to about −40° C., or about −10 to about −40° C.

Cryoprotectant can be intermittently or continuously delivered to thesurface of the patient's skin for a period of time which is short enoughto not significantly inhibit the initiation of the partial or totalfreeze event in dermal tissue but is long enough to provide substantialprotection to non-targeted tissue (e.g., subcutaneous adipose tissue).The rate of cryoprotectant delivery can be selected based on thecharacteristics of the cryoprotectant and the desired amount of tissueprotection. In one specific treatment process, an interface member isplaced directly over the target area, and the treatment device with adisposable sleeve or liner is placed in contact with the interfacemember. The interface member can be a cotton pad, gauze pad, a pouch, ora container with a reservoir containing a volume of cryoprotectant orother flowable conductive substance. The interface member can include,for example, a non-woven cotton fabric pad saturated with the substancethat delivers cryoprotectant at a desired delivery rate. Suitable padsinclude Webril™ pads manufactured by Covidien of Mansfield, Mass.Further details regarding the interface member and associated systemsand methods are described in commonly-assigned U.S. Patent PublicationNo. 2010/0280582.

In a certain embodiment, the system 100 (FIG. 2) can be used to performseveral treatment methods without using a chemical cryoprotectant. FIG.5B is a flow diagram illustrating a method 500 for improving theappearance of skin without any chemical composition in accordance withembodiments of the disclosure. As shown in FIG. 5B, an early stage ofthe method 500 can include cooling a surface of a human subject's skinto a first temperature (block 502). The first temperature can be, forexample, between about −5° C. and −40° C. such that a portion of tissuebelow the surface is in a supercooled state. The supercooled tissue caninclude epidermal tissue, dermal tissue, subcutaneous tissue, othertissue, and combinations thereof.

The method 500 can also include heating the surface of the humansubject's skin in an amount sufficient to raise the temperature of thesurface or upper layer of tissue from the first temperature to a secondtemperature that is a non-supercooled temperature. Deeper tissue belowthe surface can remain in the supercooled state (block 504). Forexample, the treatment system can be used to heat the surface (e.g., anupper portion of the epidermis) of the skin to a temperature greaterthan about 0° C. while underlying tissue remains supercooled. In someembodiments, tissue of the skin at a depth of less than about 0.2 mm,0.5 mm, or 1 mm are warmed to a non-supercooled state. The temperatureof the skin surface can be increased about 40° C., 30° C. 20° C., 10° C.during the warming period (e.g., 0.5 second, 1 second, 2 seconds, 5seconds, etc.). The surface of the skin can be periodically heated tominimize or limit thermal damage while deeper tissue is at or below thetreatment temperature (e.g., a temperature for supercooling).

In block 506, the method 500 can further include nucleating thesupercooled portion of tissue below warmed tissue to cause at least somecells in the supercooled tissue to at least partially freeze. In oneembodiment, nucleation of the supercooled tissue is caused by amechanical perturbation (e.g., vibration, ultrasound pulses, etc.) whilewarmed cells residing at the surface of the human subject's skin do notfreeze. This allows for localized nucleation and protection of cells atthe surface can be accomplished without the use of a chemicalcryoprotectant. Optionally, a cryoprotectant may also be used to providefurther protection for epidermal tissue to minimize any undue damagethereto which might result in a hyperpigmentation or hypopigmentationresponse sometime after completing treatment. In various embodiments,the supercooled tissue can comprise some portion of the epidermal tissue(e.g., a lower region of epidermal tissue), dermal tissue, connectivetissue, subcutaneous tissue, or other tissue targeted to experience afreeze injury.

In certain embodiments, the method 500 may further include maintainingthe supercooled tissue in at least a partially or totally frozen statefor a predetermined period of time (block 508). For example, thesupercooled tissue can be maintained in the at least partially ortotally frozen state for longer than about 2 seconds, 5 seconds, 10seconds, 12 seconds, 15 seconds, or 20 seconds. In various arrangements,the supercooled tissue can be maintained in the at least partially ortotally frozen state for a duration of time sufficient to improve anappearance of skin or provide for other treatments (e.g., tightening theskin, increasing skin smoothness, thickening the skin, improving theappearance of cellulite, improving acne, improving a quality of hair,improving a condition associated with hyperhidrosis, etc.). In certainembodiments, the maintaining the freeze event can include detecting atemperature of the portion of tissue and controlling the cooling andheating to maintain at least a portion of the tissue in at least apartially or totally frozen state for the predetermined time (e.g.,greater than about 10 seconds, greater than about 12 seconds, greaterthan about 15 seconds, or greater than about 20 seconds).

Referring back to FIG. 5A, and at block 164, the treatment device canrapidly cool the surface of the patient's skin to a sufficiently lowtemperature to cause a partial or total freeze event in targeted tissue.The rapid cooling can create a thermal gradient with the coldesttemperatures near the applicator (e.g., the upper layers of skin). Theresulting thermal gradient causes the temperature of the upper layer(s)of the skin to be lower than that of the targeted deeper cells. Thisallows the skin to be frozen for a short enough duration so thattemperature equilibrium is not established across the skin and adjacentsubcutaneous tissue, typically adipose tissue. A cryoprotectant and/orwarming cycle can be used to inhibit freezing the uppermost non-targetedlayer, or layers, of skin, particularly epidermal tissue, so as toprevent or minimize any chance of creating hyperpigmentation orhypopigmentation.

A partial freeze event can include at least some crystallization (e.g.,formation of microscopic ice crystals) in intercellular material (e.g.,fluid, cell components, etc.) and/or extracellular fluid. By avoidingextensive ice crystal formation that would cause frostbite or necrosis,partial freeze events can occur without undesired tissue damage. Inaddition, total freeze events can be created which are maintained for aperiod of time which is kept short enough so as to not cause anundesired amount of tissue damage. In some embodiments, the surface ofthe patient's skin can be cooled to a temperature no lower than about−40° C., −30° C., −20° C., −10° C., or −5° C. to produce a partial ortotal freeze event in the skin without causing irreversible skin damage.For example, the treatment system 100 of FIG. 2 can cool the skin to atemperature in a range from about −40° C. to about 0° C. In anotherexample, the surface of the patient's skin can be cooled to from about−40° C. to about 0° C., from about −30° C. to about 0° C., from about−20° C. to about −5° C., or from about −15° C. to about −5° C. Infurther examples, the surface of the patient's skin can be cooled tobelow about −10° C., or in yet another embodiment, from about −25° C. toabout −15° C. It will be appreciated that the skin surface can be cooledto other temperatures based on the mechanism of action.

To perform cryotherapy, the cooling period can be sufficiently short tominimize, limit, or substantially eliminate necrosis, or other unwantedthermal damage, due to the freeze event. In one procedure, theapplicator (e.g., applicator 104 of FIGS. 1B and 2) can produce a freezeevent that begins within a predetermined period of time after theapplicator begins cooling the patient's skin or after the freeze eventbegins. The predetermined period of time can be equal to or less thanabout 30, 60, 90, 120, or 150 seconds and, in some embodiments, thepredetermined period of time can be from about 30 seconds to about 150seconds. A controller (e.g., controller 114 of FIG. 2) can select thepredetermined period of time based on the treatment temperatures,treatment sites, and/or cryotherapy to be performed. Alternatively, anoperator can select the period of time for cooling and can enter it intothe controller 114.

To help initiate the freeze event (e.g., the partial or total freezeevent), a substance, energy, and/or pressure can be used to aid in theformation of nucleation sites for crystallization. Substances thatpromote nucleation can be applied topically before and/or during skincooling. The energy for promoting nucleation can include, withoutlimitation, acoustic energy (e.g., ultrasound energy), mechanical energy(e.g., vibratory motion, massaging, and/or pulsatile forces), or otherenergy. The energy can also comprise alternating current electricalenergy. A nucleating substance can also optionally be applied to theskin. The applicators disclosed herein can include one or more actuators(e.g., motors with eccentric weights), vibratory motors, hydraulicmotors, electric motors, pneumatic motors, solenoids, piezoelectricshakers, and so on for providing mechanical energy, pressure, etc.Pressure for promoting nucleation can be applied uniformly ornon-uniformly across the treatment site. The applicators can alsoinclude AC electrodes. For example, the applicator 104 of FIG. 1B caninclude one or more elements 155 in the form of actuators, motors,solenoids, piezoelectric shakers, transducers (e.g., ultrasoundtransducers), electrodes (e.g., electrical electrodes, RF electrodes,etc.), or combinations thereof. Substances that promote nucleation canbe applied topically before and/or during skin cooling.

At block 166, the treatment device can detect the partial or totalfreeze event in the patient's skin using one or more electricalcomponents. FIG. 1B shows the applicator 104 with an electroniccomponent in the form of a sensor 167 that can identify positive(increase) or negative (decrease) temperature changes. During cooling,targeted tissue can reach a temperature below the freezing point of itsbiological tissue and fluids (e.g., approximately −1.8° C.). As tissue,lipids, and fluids freeze, crystals can form and energy associated withthe latent heat of crystallization of the tissue is released. Arelatively small positive change in tissue temperature can indicate apartial freeze event whereas a relatively large positive change intissue temperature can indicate a complete freeze event. The sensor 167(FIG. 1B) can detect the positive change in tissue temperature, and thetreatment system can identify it as a freeze event. The treatment systemcan be programmed to prevent small variations in temperature fromcausing false alarms with respect to false treatment events.Additionally or alternatively, the treatment system disclosed herein maydetect changes in the temperature of its components or changes in powersupplied to the treatment device (e.g., treatment devices receive morepower from the system to provide additional cooling). For example, thesensor 167 can detect changes in temperature of the applicator 104 asthe applicator gets colder in order to cool the tissue warmed bycrystallization.

Referring now to FIG. 2, the system 100 can monitor the location and/ormovement of the applicator 104 and may prevent false or inaccuratedeterminations of treatment events based on such monitoring. Theapplicator 104 may move during treatment which may cause the applicator104 to contact a warmer area of skin, to no longer contact the skin, andso on. This may cause the system 100 to register a difference intemperature that is inconsistent with a normal treatment. The controller114 may be programmed to differentiate between these types oftemperature increases and a temperature increase associated with atreatment event. U.S. Pat. No. 8,285,390 discloses techniques formonitoring and detecting freeze events and applicator movement and isincorporated by reference in its entirety. Additionally, the treatmentsystem 100 can provide an indication or alarm to alert the operator tothe source of this temperature increase. In the case of a temperatureincrease not associated with a treatment event, the system 100 may alsosuppress false indications, while in the case of a temperature increaseassociated with freezing, the system 100 take any number of actionsbased on that detection as described elsewhere herein.

The system 100 can use optical techniques to detect events at block 166of FIG. 5A. For example, the sensor 167 of FIG. 1B can be an opticalsensor capable of detecting changes in the optical characteristics oftissue caused by freezing. The optical sensor can include one or moreenergy emitters (e.g., light sources, light emitting diodes, etc.),detector elements (e.g., light detectors), or other components fornon-invasively monitoring optical characteristics of tissue. In place ofor in conjunction with monitoring using optical techniques, tissue canbe monitored using electrical and/or mechanical techniques becausechanges in electrical impedance and/or mechanical properties of thetissue can be detected and may indicate freezing of tissue. Inembodiments for measuring electrical impedance, the sensor 167 (FIG. 1B)can include two electrodes that can be placed in electricalcommunication with the skin for monitoring electrical energy travelingbetween the electrodes via the tissue. In embodiments for measuringmechanical properties, the sensor 167 can comprise one or moremechanical sensors which can include, without limitation, force sensors,pressure sensors, and so on.

At block 168, the partial or total freeze event can be maintained bycontinuously or periodically cooling the patient's tissue to keep atarget volume of skin frozen for a period of time, which can be longenough to affect the skin and thereby improve skin appearance. In shorttreatments, the period of time can be equal to or shorter than about 5,10, 15, 20, or 25 seconds. In longer treatments, the period of time canbe equal to or longer than about 25 seconds, 30 seconds, 45 seconds or1, 2, 3, 4, 5, or 10 minutes. In some procedures, the applicator 104 ofFIGS. 1B and 2 can be controlled so that the skin is partially orcompletely frozen for no longer than, for example, 5 minutes, 10minutes, 20 minutes, 30 minutes, 45 minutes, or 1 hour. In someexamples, the skin is frozen for about 1 minute to about 5 minutes,about 5 minutes to about 10 minutes, about 10 minutes to about 20minutes, or about 20 minutes to about 30 minutes. The length of time theskin is kept frozen can be selected based on severity of the freezeinjury.

At block 168 of FIG. 5A, the treatment system can control the applicatorso that the partial or total freeze event causes apoptotic damage to thetarget tissue and does not cause necrotic damage to non-targeted tissue.The cooling period can be sufficiently short to avoid or limit permanenttissue damage and, in some embodiments, can be less than about, forexample, 5 minutes, 10 minutes, 15 minutes, 20 minutes, 25 minutes, 30minutes, 35 minutes, 40 minutes, 45 minutes, 50 minutes, 55 minutes, or1 hour. In one example, the applicator produces a partial freeze eventshort enough to prevent establishing equilibrium temperature gradientsin the patient's skin. This allows freezing of shallow targeted tissuewithout substantially affecting deeper non-targeted tissue. Moreover,cells in the dermal tissue can be affected to a greater extent than thecells in the subcutaneous layer. For example, skin cells can be reducedin size or number to a greater extent than subcutaneous cells, includinglipid-rich cells. In some procedures, the subcutaneous layer can be keptat a sufficiently high temperature (e.g., at or above 0° C.) to preventany freeze event in the subcutaneous layer while the shallower skintissue experiences the partial or total freeze event. Cryoprotectant canbe used to protect the subcutaneous layer. Topical cryoprotectants canbe absorbed by the skin and can ultimately reach the subcutaneous layer.Cryoprotectant can be injected directly into the subcutaneous layerbefore performing the cooling cycle.

In some embodiments, the freeze event can occur in the epidermal layerto injure, reduce, or disrupt the epidermal cells without substantiallyinjuring, reducing, or disrupting dermal cells and/or subcutaneouscells. In other embodiments, the freeze event can occur in the dermallayer to injure, reduce, or disrupt dermal cells without substantiallyinjuring, reducing, or disrupting epidermal cells and/or subcutaneouscells. A cryoprotectant can be used to protect the epidermal layer toavoid causing long-lasting or permanent hyperpigmentation orhypopigmentation. For example, a cryoprotectant can be delivered to thesurface of the patient's skin for a period of time which is short enoughto not significantly inhibit the initiation of the partial or totalfreeze event in dermal tissue, but the period of time can be long enoughto provide substantial protection to epidermal tissue. Thecryoprotectant can prevent permanent hyperpigmentation orhypopigmentation of epidermal tissue due to tissue cooling, and thecryoprotectant delivery time and rate can be selected based on thecryoprotectant's ability to protect tissue. In one embodiment, thecryoprotectant prevents hyperpigmentation or hypopigmentation of theskin surface and also prevents damage of the epidermal tissue due totissue cooling. In yet other embodiments, the freeze event can occur inthe epidermal and dermal layers to injure, reduce, or disrupt theepidermal and dermal cells without substantially injuring, reducing, ordisrupting subcutaneous tissue to avoid body contouring. Such treatmentsare well suited for improving the appearance of skin along the face,including wrinkled, loose, and/or sagging skin around the eyes andmouth.

Certain treatment protocols can include sequentially targeting differentlayers. A first treatment session can target the epidermal layer and asubsequent additional treatment sessions can target the other layers.Different layers can be targeted in a different protocol.

The treatment system can also control operation of the applicator tothermally injure the patient's skin to cause fibrosis, which increasesthe amount of connective tissue in a desired tissue layer (e.g.,epidermis and/or dermis) to increase the firmness and appearance of theskin. In other treatments, the treatment system controls the applicatorto supercool at least a portion of tissue below the skin layer. Aperturbation (e.g., a mechanical perturbation) can be used to nucleatethe supercooled tissue to at least partially or totally freeze thetissue. Alternating electric fields can be used to create nucleationperturbations. Various substances can be applied to the treatment siteto facilitate nucleation of supercooled tissue.

At block 169, the patient's partially or completely frozen skin can bethawed by heating it in order to minimize, reduce, or limit tissuedamage. The applicator (e.g., applicator 104 of FIG. 2) can thaw thepatient's skin, or other frozen tissue, after the freeze event occursand after a period of time has transpired. The period of time can beequal to or shorter than about 5, 10, 15, 20, or 25 seconds or about 1,2, 3, 4, 5, or 10 minutes. In one example, the uppermost skin layer(s)can be periodically heated to a temperature above the skin's freezingpoint to provide freeze protection thereto. The thermal elements can beresistive heaters, electromagnetic energy emitters, Peltier devices,etc. In some embodiments, the applicator 104 of FIGS. 1B and 2 can havecooling elements and separate heating elements that can cooperate toprovide precise temperature control of freezing and thawing/warmingcycles. Alternatively, the applicator 104 may stop or reduce tissuecooling to allow cooled tissue to naturally warm and thaw. Thus, tissuecan be actively or passively thawed.

The applicator 104 (FIG. 2) can thaw the patient's skin, or other frozentissue, after the freeze event occurs and after the period of time hastranspired to reduce and control freeze damage. In one example, theuppermost skin layer can be periodically heated to a temperature abovethe skin's freezing point to provide freeze protection thereto. In someprocedures, the applicator 104 repeatedly freezes and thaws tissue tocontrol thermal injuries to that tissue.

The system 100 can be used to perform several different cryotherapyprocedures. Although specific methods are described in connection withFIGS. 3-5B, one skilled in the art is capable of identifying othermethods that the system 100 could perform. Additionally, the treatmentsystem 100 of FIG. 6 can perform the methods described in connectionwith FIGS. 3-5B. Applicators are discussed in connection with FIGS. 7-9and can be used with the system 100 (FIGS. 2 and 6) or differenttreatment systems to perform the procedures disclosed herein.

FIG. 6 is a partially schematic isometric view of the system 100 with amulti-modality applicator 204 positioned along the subject's waist. Thepower supply 110 can provide a direct current voltage to the applicator204 to remove heat from the subject 101. The controller 114 can monitorprocess parameters via sensors (e.g., sensors of the applicator 204and/or sensors placed proximate to the applicator 204) via the controlline 116 to, among other things, adjust the heat removal rate and/orenergy delivery rate based on a custom treatment profile orpatient-specific treatment plan, such as those described, for example,in commonly assigned U.S. Pat. No. 8,275,442.

The controller 114 can exchange data with the applicator 204 via anelectrical line 112 or, alternatively, via a wireless or an opticalcommunication link. The control line 116 and electrical line 112 areshown without any support structure. Alternatively, control line 116 andelectrical line 112 (and other lines including, but not limited to fluidlines 108 a-b and power lines 109 a-b) may be bundled into or otherwiseaccompanied by a conduit or the like to protect such lines, enhanceergonomic comfort, minimize unwanted motion (and thus potentialinefficient removal of heat from and/or delivery of energy to subject101), and to provide an aesthetic appearance to the system 100. Examplesof such a conduit include a flexible polymeric, fabric, compositesheath, an adjustable arm, etc. Such a conduit (not shown) may bedesigned (via adjustable joints, etc.) to “set” the conduit in place forthe treatment of the subject 101.

The controller 114 can receive data from an input/output device 120,transmit data to a remote output device (e.g., a computer), and/orexchange data with another device. The input/output device 120 caninclude a display or touch screen (shown), a printer, video monitor, amedium reader, an audio device such as a speaker, any combinationthereof, and any other device or devices suitable for providing userfeedback. In the embodiment of FIG. 6, the input/output device 120 canbe a touch screen that provides both an input and output functionality.The treatment tower 102 can include visual indicator devices or controls(e.g., indicator lights, numerical displays, etc.) and/or audioindicator devices or controls. These features can be part of a controlpanel that may be separate from the input/output device 120, may beintegrated with one or more of the devices, may be partially integratedwith one or more of the devices, may be in another location, and so on.In alternative examples, input/output device 120 or parts thereof(described herein) may be contained in, attached to, or integrated withthe applicator 204.

The controller 114, power supply 110, chiller unit 106 with a reservoir105, and input/output device 120 are carried by a rack 124 with wheels126 for portability. In alternative embodiments, the controller 114 canbe contained in, attached to, or integrated with the multi-modalityapplicator 204 and/or a patient protection device. In yet otherembodiments, the various components can be fixedly installed at atreatment site. Further details with respect to components and/oroperation of applicators, treatment tower, and other components may befound in commonly-assigned U.S. Patent Publication No. 2008/0287839.

The system 100 can include an energy-generating unit 107 for applyingenergy to the target region, for example, to further interrogate cooledor heated cells via power-lines 109 a-b. In one embodiment, theenergy-generating unit 107 can be a pulse generator, such as a highvoltage or low voltage pulse generator, capable of generating anddelivering a high or low voltage current, respectively, through thepower lines 109 a, 109 b to one or more electrodes (e.g., cathode,anode, etc.) in the applicator 204. In other embodiments, theenergy-generating unit 107 can include a variable powered RF generatorcapable of generating and delivering RF energy, such as RF pulses,through the power lines 109 a, 109 b or to other power lines (notshown). RF energy can be directed to non-targeted tissue to help isolatecooling. For example, RF energy can be delivered to non-targeted tissue,such as subdermal tissue, to inhibit or prevent damage to suchnon-targeted tissue. In a further embodiment, the energy-generating unit107 can include a microwave pulse generator, an ultrasound pulse lasergenerator, or high frequency ultrasound (HIFU) phased signal generator,or other energy generator suitable for applying energy. In additionalembodiments, the system 100 can include more than one energy-generatorunit 107 such as any one of a combination of the energy modalitygenerating units described herein. Systems having energy-generatingunits and applicators having one or more electrodes are described incommonly assigned U.S. Patent Publication No. 2012/0022518 and U.S.patent application Ser. No. 13/830,413.

The applicator 204 can include one or more heat-exchanging units. Eachheat-exchanging unit can include or be associated with one or morePeltier-type thermoelectric elements, and the applicator 204 can havemultiple individually controlled heat-exchanging zones (e.g., between 1and 50, between 10 and 45; between 15 and 21, etc.) to create a customspatial cooling profile and/or a time-varying cooling profile. Eachcustom treatment profile can include one or more segments, and eachsegment can include a specified duration, a target temperature, andcontrol parameters for features such as vibration, massage, vacuum, andother treatment modes. Applicators having multiple individuallycontrolled heat-exchanging units are described in commonly assigned U.S.Patent Publication Nos. 2008/0077211 and 2011/0238051.

The applicator 204 can be applied with pressure or with a vacuum typeforce to the subject's skin. Pressing against the skin can beadvantageous to achieve efficient treatment. In general, the subject 101has an internal body temperature of about 37° C., and the bloodcirculation is one mechanism for maintaining a constant bodytemperature. As a result, blood flow through the tissue to be treatedcan be viewed as a heat source that counteracts the cooling of thedesired targeted tissue. As such, cooling the tissue of interestrequires not only removing the heat from such tissue but also that ofthe blood circulating through this tissue. Thus, temporarily reducing oreliminating blood flow through the treatment region, by means such as,e.g., applying the applicator with pressure, can improve the efficiencyof tissue cooling (e.g., tissue cooling to reduce cellulite, wrinkles,sagging skin, loose skin, etc.), and avoid excessive heat loss.Additionally, a vacuum can pull tissue away from the body which canassist in cooling targeted tissue.

FIG. 7 is a schematic cross-sectional view illustrating a treatmentdevice in the form an applicator 200 for non-invasively removing heatfrom target tissue in accordance with an embodiment of the presenttechnology. The applicator 200 can include a cooling device 210 and aninterface layer 220. In one embodiment, the cooling device 210 includesone or more thermoelectric elements 213 (e.g., Peltier-type TECelements) powered by the treatment tower (e.g., treatment tower 102 ofFIGS. 2 and 6).

The applicator 200 can contain a communication component 215 thatcommunicates with the controller 114 to provide a first sensor reading242, and a sensor 217 that measures, e.g., temperature of the coolingdevice 210, heat flux across a surface of or plane within the coolingdevice 210, tissue impedance, application force, tissue characteristics(e.g., optical characteristics), etc. The interface layer 220 can be aplate, a film, a covering, a sleeve, a substance reservoir or othersuitable element described herein and, in some embodiments, may serve asthe patient protection device described herein.

The interface layer 220 can also contain a similar communicationcomponent 225 that communicates with the controller 114 to provide asecond sensor reading 244 and a sensor 227 that measures, e.g., the skintemperature, temperature of the interface layer 220, heat flux across asurface of or plane within the interface layer 220, contact pressurewith the skin 230 of the patient, etc. For example, one or both of thecommunication components 215, 225 can receive and transmit informationfrom the controller 114, such as temperature and/or heat fluxinformation as determined by one or both of sensors 217, 227. Thesensors 217, 227 are configured to measure a parameter of the interfacewithout substantially impeding heat transfer between the heat-exchangingplate 210 and the patient's skin 230. The applicator 200 can alsocontain components described in connection with FIGS. 2 and 6.

In certain embodiments, the applicator 200 can include a sleeve or liner250 (shown schematically in phantom line) for contacting the patient'sskin 230, for example, to prevent direct contact between the applicator200 and the patient's skin 230, and thereby reduce the likelihood ofcross-contamination between patients, minimize cleaning requirements forthe applicator 200, etc. The sleeve 250 can include a first sleeveportion 252 and a second sleeve portion 254 extending from the firstsleeve portion. The first sleeve portion 252 can contact and/orfacilitate the contact of the applicator 200 with the patient's skin230, while the second sleeve portion 254 can be an isolation layerextending from the first sleeve portion 252. The second sleeve portion254 can be constructed from latex, rubber, nylon, Kevlar®, or othersubstantially impermeable or semi-permeable material. The second sleeveportion 254 can prevent contact between the patient's skin 230 and theheat-exchanging plates 210, among other things. Further detailsregarding a patient protection device may be found in U.S. PatentPublication No. 2008/0077201.

A device (not shown) can assists in maintaining contact between theapplicator 200 (such as via an interface layer 220) and the patient'sskin 230. The applicator 200 can include a belt or other retentiondevices (not shown) for holding the applicator 200 against the skin 230.The belt may be rotatably connected to the applicator 200 by a pluralityof coupling elements that can be, for example, pins, ball joints,bearings, or other type of rotatable joints. Alternatively, retentiondevices can be rigidly affixed to the end portions of the interfacelayer 220. Further details regarding a suitable belt devices orretention devices may be found in U.S. Patent Publication No.2008/0077211.

A vacuum can assist in forming a contact between the applicator 200(such as via the interface layer 220 or sleeve 250) and the patient'sskin 230. The applicator 200 can provide mechanical energy to atreatment region using the vacuum. Imparting mechanical vibratory energyto the patient's tissue by repeatedly applying and releasing (orreducing) the vacuum, for instance, creates a massage action duringtreatment. Further details regarding vacuums and vacuum type devices maybe found in U.S. Patent Application Publication No. 2008/0287839.

FIGS. 8A to 8C illustrate treatment devices suitable for use with thesystem 100 of FIGS. 2 and 6 in accordance with embodiments of thetechnology. FIG. 8A is a schematic, cross-sectional view illustrating anapplicator 260 for non-invasively removing heat from target areas of asubject 262. The applicator 260 can include a heat-exchanging unit orcooling device, such as a heat-exchanging plate 264 (shown in phantomline) and an interface layer 265 (shown in phantom line). The interfacelayer 265 can have a rigid or compliant concave surface 267. When theapplicator 260 is held against the subject, the subject's tissue can bepressed against the curved surface 267. One or more vacuum ports can bepositioned along the surface 267 to draw the skin 262 against thesurface 267. The configuration (e.g., dimensions, curvature, etc.) ofthe applicator 260 can be selected based on the treatment site.

FIG. 8B is a schematic, cross-sectional view illustrating an applicator270 that can include a heat-exchanging unit 274 having a rigid orcompliant convex surface 276 configured to be applied to concave regionsof the subject 272. Advantageously, the convex surface 276 can spreadtissue to reduce the distance between the convex surface 276 andtargeted tissue under the convex surface 276.

FIG. 8C is a schematic, cross-sectional view illustrating an applicator280 including a surface 282 movable between a planar configuration 284and a non-planar configuration 285 (shown in phantom). The surface 282is capable of conforming to the treatment site to provide a largecontact area. In some embodiments, the surface 282 can be sufficientlycompliant to conform to highly contoured regions of a subject's facewhen the applicator 280 is pressed against facial tissue. In otherembodiments, the applicator 280 can include actuators or other devicesconfigured to move the surface 282 to a concave configuration, a convexconfiguration, or the like. The surface 282 can be reconfigured to treatdifferent treatment sites of the same subject or multiple subjects.

FIG. 9 is a schematic, cross-sectional view of an applicator 300 fornon-invasively removing heat from target areas in accordance withanother embodiment of the technology. The applicator 300 includes ahousing 301 having a vacuum cup 302 with a vacuum port 304 disposed inthe vacuum cup 302. The housing 301 is coupled to or otherwise supportsa first applicator unit 310 a on one side of the cup 302, and a secondapplicator unit 310 b on an opposing side of the cup 302. Each of thefirst and second applicator units 310 a, 310 b can include aheat-exchanging unit (e.g., a cooling unit, heating/cooling device,etc.) with a heat-exchanging plate 312 (shown individually as 312 a and312 b), and an interface layer 314 (shown individually as 314 a and 314b). In one embodiment, the heat-exchanging plate 312 is associated withone or more Peltier-type TEC elements supplied with coolant and powerfrom the treatment tower 102 (FIGS. 2 and 6). As such, theheat-exchanging plates 312 a, 312 b can be similar to theheat-exchanging plate 210 described above with reference to FIG. 7.

The interface layers 314 a and 314 b are adjacent to the heat-exchangingplates 312 a and 312 b, respectively. Similar to the interface layer 220illustrated in FIG. 7, the interface layers 314 a and 314 b can beplates, films, a covering, a sleeve, a reservoir or other suitableelement located between the heat-exchanging plates 312 a and 312 b andthe skin (not shown) of a subject. In one embodiment, the interfacelayers 314 a and 314 b can serve as patient protection devices and caninclude communication components (not shown) and sensors (not shown)similar to those described with respect to the interface layer 220 ofFIG. 7 for communicating with the controller 114. In other embodiments,the interface layers 314 can be eliminated.

In operation, a rim 316 of the vacuum cup 302 is placed against the skinof a subject and a vacuum is drawn within the cup 302. The vacuum pullsthe tissue of the subject into the cup 302 and coats the target areawith the interface layers 314 a and 314 b of the corresponding first andsecond applicator units 310 a, 310 b. One suitable vacuum cup 302 withcooling units is described in U.S. Pat. No. 7,367,341. The vacuum canstretch or otherwise mechanically challenge skin. Applying theapplicator 300 with pressure or with a vacuum type force to thesubject's skin or pressing against the skin can be advantageous toachieve efficient treatment. The vacuum can be used to damage (e.g., viamechanically massage) and/or stretch connective tissue, thereby lengthenthe connective tissue. In general, the subject has an internal bodytemperature of about 37° C., and the blood circulation is one mechanismfor maintaining a constant body temperature. As a result, blood flowthrough the skin and subcutaneous layer of the region to be treated canbe viewed as a heat source that counteracts the cooling of the desiredtargeted tissue. As such, cooling the tissue of interest requires notonly removing the heat from such tissue but also that of the bloodcirculating through this tissue. Temporarily reducing or eliminatingblood flow through the treatment region, by means such as, e.g.,applying the applicator with pressure, can improve the efficiency oftissue cooling and avoid excessive heat loss through the dermis andepidermis. Additionally, a vacuum can pull skin away from the body whichcan assist in cooling targeted tissue.

The units 310 a and 310 b can be in communication with a controller(e.g., the controller 114 of FIGS. 2 and 6), and a supply such that theheat-exchanging plates 312 a, 312 b can provide cooling or energy to thetarget region based on a predetermined or real-time determined treatmentprotocol. For example, the heat-exchanging plates 312 a, 312 b can firstbe cooled to cool the adjacent tissue of the target region to atemperature below 37° C. (e.g., to a temperature in the range of betweenabout −40° C. to about 20° C.). The heat-exchanging plates 312 a, 312 bcan be cooled using Peltier devices, cooling channels (e.g., channelsthrough which a chilled fluid flows), cryogenic fluids, or other similarcooling techniques. In one embodiment, the heat-exchanging plates 312 a,312 b are cooled to a desired treatment temperature (e.g., −40° C., −30°C., −25° C., −20° C., −18° C., −15° C., −10° C., −5° C., 0° C., or 5°C.). In this example, the lipid-rich cells can be maintained at asufficiently low temperature to be damaged or destroyed.

E. Suitable Computing Environments

FIG. 10 is a schematic block diagram illustrating subcomponents of acomputing device 700 suitable for the system 100 of FIGS. 2 and 6 inaccordance with an embodiment of the disclosure. The computing device700 can include a processor 701, a memory 702 (e.g., SRAM, DRAM, flash,or other memory devices), input/output devices 703, and/or subsystemsand other components 704. The computing device 700 can perform any of awide variety of computing processing, storage, sensing, imaging, and/orother functions. Components of the computing device 700 may be housed ina single unit or distributed over multiple, interconnected units (e.g.,though a communications network). The components of the computing device700 can accordingly include local and/or remote memory storage devicesand any of a wide variety of computer-readable media. In someembodiments, the input/output device 703 can be the input/output device120 of FIG. 6.

As illustrated in FIG. 10, the processor 701 can include a plurality offunctional modules 706, such as software modules, for execution by theprocessor 701. The various implementations of source code (i.e., in aconventional programming language) can be stored on a computer-readablestorage medium or can be embodied on a transmission medium in a carrierwave. The modules 706 of the processor can include an input module 708,a database module 710, a process module 712, an output module 714, and,optionally, a display module 716.

In operation, the input module 708 accepts an operator input 719 via theone or more input/output devices described above with respect to FIG. 6,and communicates the accepted information or selections to othercomponents for further processing. The database module 710 organizesrecords, including patient records, treatment data sets, treatmentprofiles and operating records and other operator activities, andfacilitates storing and retrieving of these records to and from a datastorage device (e.g., internal memory 702, an external database, etc.).Any type of database organization can be utilized, including a flat filesystem, hierarchical database, relational database, distributeddatabase, etc.

In the illustrated example, the process module 712 can generate controlvariables based on sensor readings 718 from sensors (e.g., sensor 167 ofFIG. 1B, the temperature measurement components 217 and 227 of FIG. 6,etc.) and/or other data sources, and the output module 714 cancommunicate operator input to external computing devices and controlvariables to the controller 114 (FIGS. 2 and 6). The display module 816can be configured to convert and transmit processing parameters, sensorreadings 818, output signals 720, input data, treatment profiles andprescribed operational parameters through one or more connected displaydevices, such as a display screen, printer, speaker system, etc. Asuitable display module 716 may include a video driver that enables thecontroller 114 to display the sensor readings 718 or other status oftreatment progression on the input/output device 120 (FIG. 6).

In various embodiments, the processor 701 can be a standard centralprocessing unit or a secure processor. Secure processors can bespecial-purpose processors (e.g., reduced instruction set processor)that can withstand sophisticated attacks that attempt to extract data orprogramming logic. The secure processors may not have debugging pinsthat enable an external debugger to monitor the secure processor'sexecution or registers. In other embodiments, the system may employ asecure field programmable gate array, a smartcard, or other securedevices.

The memory 702 can be standard memory, secure memory, or a combinationof both memory types. By employing a secure processor and/or securememory, the system can ensure that data and instructions are both highlysecure and sensitive operations such as decryption are shielded fromobservation.

Suitable computing environments and other computing devices and userinterfaces are described in commonly assigned U.S. Pat. No. 8,275,442,entitled “TREATMENT PLANNING SYSTEMS AND METHODS FOR BODY CONTOURINGAPPLICATIONS,” which is incorporated herein in its entirety byreference.

F. Conclusion

It will be appreciated that some well-known structures or functions maynot be shown or described in detail, so as to avoid unnecessarilyobscuring the relevant description of the various embodiments. Althoughsome embodiments may be within the scope of the technology, they may notbe described in detail with respect to the Figures. Furthermore,features, structures, or characteristics of various embodiments may becombined in any suitable manner. The technology disclosed herein can beused to perform the procedures disclosed in U.S. Provisional ApplicationSer. Nos. 61/943,257 and 61/943,251, both filed Feb. 21, 2014, U.S. Pat.No. 7,367,341 entitled “METHODS AND DEVICES FOR SELECTIVE DISRUPTION OFFATTY TISSUE BY CONTROLLED COOLING” to Anderson et al., and U.S. PatentPublication No. US 2005/0251120 entitled “METHODS AND DEVICES FORDETECTION AND CONTROL OF SELECTIVE DISRUPTION OF FATTY TISSUE BYCONTROLLED COOLING” to Anderson et al., the disclosures of which areincorporated herein by reference in their entireties. The technologydisclosed herein can target tissue for tightening the skin, improvingskin tone or texture, eliminating or reducing wrinkles, increasing skinsmoothness as disclosed in U.S. Provisional Application Ser. No.61/943,250.

Unless the context clearly requires otherwise, throughout thedescription, the words “comprise,” “comprising,” and the like are to beconstrued in an inclusive sense as opposed to an exclusive or exhaustivesense; that is to say, in a sense of “including, but not limited to.”Words using the singular or plural number also include the plural orsingular number, respectively. Use of the word “or” in reference to alist of two or more items covers all of the following interpretations ofthe word: any of the items in the list, all of the items in the list,and any combination of the items in the list. In those instances where aconvention analogous to “at least one of A, B, and C, etc.” is used, ingeneral such a construction is intended in the sense of the convention(e.g., “a system having at least one of A, B, and C” would include butnot be limited to systems that have A alone, B alone, C alone, A and Btogether, A and C together, B and C together, and/or A, B, and Ctogether, etc.). In those instances where a convention analogous to “atleast one of A, B, or C, etc.” is used, in general such a constructionis intended in the sense of the convention (e.g., “a system having atleast one of A, B, or C” would include but not be limited to systemsthat have A alone, B alone, C alone, A and B together, A and C together,B and C together, and/or A, B, and C together, etc.).

Any patents, applications and other references, including any that maybe listed in accompanying filing papers, are incorporated herein byreference. Aspects of the described technology can be modified, ifnecessary, to employ the systems, functions, and concepts of the variousreferences described above to provide yet further embodiments. While theabove description details certain embodiments and describes the bestmode contemplated, no matter how detailed, various changes can be made.Implementation details may vary considerably, while still beingencompassed by the technology disclosed herein. The various aspects andembodiments disclosed herein are for purposes of illustration and arenot intended to be limiting, with the true scope and spirit beingindicated by the following claims.

What is claimed is:
 1. A method for improving the appearance of skin bytightening the skin, improving skin tone or texture, eliminating orreducing wrinkles, increasing skin smoothness, or improving theappearance of cellulite, the method comprising: cooling a surface of apatient's skin at a treatment site to a temperature in a range of about−30 degrees C. to about −5 degrees C.; detecting a freeze event in thepatient's skin; and controlling a cooling device to continue cooling thepatient's skin after the freeze event is detected and to maintain atleast a partially frozen state of a tissue at the treatment site for aperiod of time longer than about 10 seconds and shorter than about 5minutes to improve the appearance of the skin, wherein the improvementin the appearance of skin does not include significant lightening ordarkening of a color of the skin such that the color of the skin at thetreatment site within one or more days after the freeze event ends issubstantially identical to the skin's color at the treatment siteimmediately prior to cooling the surface.
 2. The method of claim 1,further comprising applying sufficient cryoprotectant to the skin toprotect epidermal tissue from freeze injury from the cooling device. 3.The method of claim 1, wherein cooling the surface of the patient's skinincludes cooling the skin using a thermoelectric applicator with thecooling device, and wherein the freeze event is detected usingelectrical components of the thermoelectric applicator.
 4. The method ofclaim 1, wherein the period of time is shorter than about 30 seconds orabout 1, 2, 3, or 4 minutes.
 5. The method of claim 1, wherein theperiod of time is selected to be short enough so that lipid rich cellsin a subcutaneous layer are not substantially affected by the cooling ofthe surface of the patient's skin.
 6. The method of claim 1, wherein theperiod of time is selected to be long enough so that lipid rich cells ina subcutaneous layer are substantially affected by the skin cooling. 7.The method of claim 1, further comprising thawing the patient's skinafter the freeze event occurs and after the period of time hastranspired to control freeze damage caused by the skin cooling.
 8. Themethod of claim 1, further comprising using optical detection techniquesand/or thermal detection techniques to detect the freeze event.
 9. Themethod of claim 1, further comprising controlling the cooling device sothat the freeze event causes apoptotic damage to the patient's skin anddoes not cause necrotic damage to subcutaneous tissue.
 10. The method ofclaim 1, further comprising controlling the cooling device so that thefreeze event is short enough such that equilibrium temperature gradientsin the patient's skin cooled by the cooling device are not established.11. The method of claim 1, further comprising controlling the coolingdevice so that the freeze event begins within a second predeterminedperiod of time after the cooling device begins cooling the skin, and thesecond predetermined period of time being shorter than about either 30seconds or shorter than about either 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10minutes.
 12. The method of claim 1, further comprising delivering asubstance, energy, pressure, and/or perturbation to the patient's skinto aid in formation of nucleation sites in the skin to initiate thefreeze event after the skin has been cooled to a supercooled state. 13.The method of claim 12, further comprising applying heat to thepatient's skin surface after the surface of the patient's skin has beensupercooled to raise a temperature of an uppermost skin layer to a levelabove a freezing point to provide freeze protection thereto prior toforming the nucleation sites.
 14. The method of claim 1, furthercomprising delivering a cryoprotectant to the surface of the patient'sskin for a period of time which is short enough to not significantlyinhibit the initiation of the freeze event in dermal tissue but is longenough to provide substantial freeze protection to epidermal tissue. 15.The method of claim 1, wherein the freeze event creates at least somemicroscopic crystal formation in intercellular fluid and/orextracellular fluid.
 16. The method of claim 1, wherein the coolingdevice is controlled to sufficiently injure the skin to cause fibrosisthat increases firmness of the skin.
 17. The method of claim 1, whereinthe freeze event causes the patient's skin to be tightened.
 18. Themethod of claim 1, wherein the freeze event causes the patient's skinsmoothness to be improved.
 19. The method of claim 1, wherein thecooling device detects the freeze event in the patient's skin.
 20. Themethod of claim 1, further comprising cooling the surface of thepatient's skin to a temperature in a range of about −25 degrees C. toabout −10 degrees C.
 21. The method of claim 1, further comprisingcooling the surface of the patient's skin to a temperature in a range ofabout −20 degrees C. to about −10 degrees C.
 22. A method for improvingthe appearance of skin by tightening the skin, improving skin tone ortexture, eliminating or reducing wrinkles, increasing skin smoothness,or improving the appearance of cellulite, the method comprising:applying a thermoelectric applicator to a surface of a patient's skin,controlling the thermoelectric applicator to cool the surface of thepatient's skin at a treatment site to a temperature in a range of about−30 degrees C. to about −5 degrees C.; detecting, via the thermoelectricapplicator, a freeze event in the patient's skin; and controlling thethermoelectric applicator to continue cooling the patient's skin afterthe freeze event is detected so as to maintain at least a partiallyfrozen state of a tissue at the treatment site for a period of timelonger than about 10 seconds and shorter than about 5 minutes to improvethe appearance of the skin without causing either hyperpigmentation orhypopigmentation of skin at the treatment site within one or more daysafter the freeze event ends.
 23. The method of claim 22, wherein thethermoelectric applicator includes a cooling device configured to coolthe surface of the patient's skin and a freeze event detector.
 24. Themethod of claim 22, wherein the thermoelectric applicator cools thesurface of the patient's skin to a temperature in a range of about −25degrees C. to about −10 degrees C.